US6169107B1ExpiredUtility
Indoloylguanidine derivatives
Est. expiryApr 28, 2013(expired)· nominal 20-yr term from priority
Inventors:Masahumi KitanoKazuhiro NakanoHideki YagiNaohito OhashiAtsuyuki KojimaTsuyoshi NoguchiAkira Miyagishi
C07D 209/08C07D 209/42
83
PatentIndex Score
31
Cited by
89
References
48
Claims
Abstract
Novel indoloylguanidine derivatives shown by formula (1), wherein R1 represents one or more, the same or different substituent(s) which is selected from the group consisting of a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a halogen atom, nitro group, an acyl group, carboxyl group, an alkoxycarbonyl group, an aromatic group, and a group shown by formula: -OR3, -NR6R7, -SO2NR6R7 or -S(O)nR40; and R2 represents a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, hydroxy group, an alkoxy group or a group shown by formula: -CH2R20; and which inhibit the Na+/H+ exchanger activity and are useful for the treatment and prevention of a disease caused by increased Na+/H+ exchanger activity, such as hypertension, arrhythmia, angina pectoris, cardiac hypertrophy, diabetes, disorders associated with ischemia or ischemic reperfusion, cerebro-ischemic disorders; or diseases caused by excessive cell proliferation.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1. An indoloylguanidine derivative represented by formula (1):
wherein:
the guanidinocarbonyl group may be located at any open position on either the 5-membered or 6-membered rings comprising the indole nucleus, x=5 so that R 1 is located at each position on the indole nucleus not occupied by the guanidinocarbonyl group, and each R 1 independently represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 2 -C 6 alkenyl group, a C 2 -C 6 alkynyl group, a C 3 -C 7 cycloalkyl group, a halogen atom, nitro, a C 2 -C 8 alkanoyl group, an arylalkanoyl group having carbon atoms up to 10, an aroyl group having carbon atoms up to 11, carboxyl, a C 2 -C 6 alkoxycarbonyl group, an aromatic group, a group shown by formula: —OR 3 , —NR 6 R 7 , —SO 2 NR 6 R 7 or —S(O) n R 40 , and a group shown by formula:
wherein A represents an oxygen atom or a group shown by formula: —S(O) n — or —N (R 50 )— (in which R 50 is a hydrogen atom or a C 1 -C 8 alkyl group; R′ represents a hydrogen atom, a C 1 -C 8 alkyl group or a substituted C 1 -C 8 alkyl group); and
represents a saturated 3 to 8-membered hetero ring containing one nitrogen atom;
R 2 represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 3 -C 7 cycloalkyl group, hydroxy, a C 1 -C 6 alkoxy group, an aromatic group or a group shown by formula: —CH 2 R 20 ;
R 3 represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 3 -C 7 cycloalkyl group, an aromatic group or a group shown by formula: —CH 2 R 30 , in which R 30 represents an C 2 -C 8 alkenyl group or an C 2 -C 6 alkynyl group;
each of R 6 and R 7 independently represents a hydrogen atom, a C 1 -C 6 alkyl group, a substituted C 1 -C 8 alkyl group, a C 3 -C 7 cycloalkyl group, a C 2 -C 8 alkanoyl group, an arylalkanoyl group having carbon atoms up to 10, an aroyl group having carbon atoms up to 11, an aromatic group or a group shown by formula: —CH 2 R 60 (in which R 60 represents a C 2 -C 6 alkenyl group or a C 2 -C 6 alkynyl group); or R 6 and R 7 are combined together to form a saturated 5- to 7-membered cyclic amino group which may contain other hetero atom(s) in the ring thereof;
R 40 represents a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group or an aromatic group;
n represents 0, 1 or 2; and,
R 20 represents a C 2 -C 6 alkenyl group or a C 2 -C 6 alkynyl group;
in which:
the substituent(s) of said substituted C 1 -C 8 alkyl group means a halogen atom, hydroxy, a C 1 -C 6 alkoxy group, cyano, a C 2 -C 8 alkanoyl group, an arylalkanoyl group having carbon atoms up to 10, an aroyl group having carbon atoms up to 11, an aromatic group, and —CONR 4 R 5 in which each of R 4 and R 5 independently represents a hydrogen atom or a C 1 -C 8 alkyl group or R 4 and R 5 are combined together to form a saturated 5- to 7-membered cyclic amino group which may contain other hetero atom(s) in the ring; —NR 6 R 7 ; or a group shown by:
in which:
E represents a nitrogen atom or a CH group and
R″ represents a hydrogen atom, a C 1 -C 8 alkyl group or a substituted C 1 -C 8 alkyl group substituted with hydroxy, a C 1 -C 8 alkoxy group, cyano, carboxyl, a C 2 -C 6 alkoxycarbonyl group, a C 2 -C 8 alkanoyl group, an arylalkanoyl group having carbon atoms up to 10, an aroyl group having carbon atoms up to 11, an aromatic group, a group shown by —NR 6 R 7 , or a group shown by —CONR 4 R 5 , in which each of R 4 and R 5 independently represents a hydrogen atom or a C 1 -C 8 alkyl group or R 4 and R 5 are combined together to form a saturated 5- to 7-membered cyclic amino group which may contain other hetero atom(s) therein; and the ring of
is a 3- to 8-membered saturated aliphatic ring or saturated hetero ring containing one nitrogen atom;
each of the aromatic groups being selected from the group consisting of (a) an aryl group having carbon atoms up to 10, (b) a 5- or 6-membered hetero-aryl group containing 1 to 4 nitrogen atom(s), (c) a 5- or 6-membered hetero-aryl group containing 1 to 2 nitrogen atom(s) and one oxygen atom or one sulfur atom, and (d) a furyl group; and,
each of the aromatic groups may be substituted with a substituent selected from the group consisting of a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a halogen atom, nitro, a C 2 -C 6 alkoxy-carbonyl group, carboxyl and a group selected from thas group shown by formulae: —OR 3 , —NR 6 R 7 , —CONR 6 R 7 , —SO 2 NR 6 R 7 and —S(O) n R 40 ;
provided that said indoloylguanidine derivative does not include 1-methyl-2-indoloylguanidine; or,
a pharmaceutically acceptable acid addition salt thereof.
2. An indoloylguanidine derivative represented by formula (1):
wherein:
the guanidinocarbonyl group may be located at any open position on either the 5-membered or 6-membered rings comprising the indole nucleus, x=5 so that R 1 is located at each position on the indole nucleus not occupied by the guanidinocarbonyl group, and each R 1 independently represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 2 -C 6 alkenyl group, a C 2 -C 6 alkynyl group, a C 3 -C 7 cycloalkyl group, a halogen atom, nitro, a C 2 -C 8 alkanoyl group, an arylalkanoyl group having carbon atoms up to 10, an aroyl group having carbon atoms up to 11, carboxyl, a C 2 -C 6 alkoxycarbonyl group, an aromatic group, and a group shown by formula: —OR 3 , —NR 6 R 7 , —SO 2 NR 6 R 7 or —S(O) n R 40 ;
R 2 represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 3 -C 7 cycloalkyl group, hydroxy, a C 1 -C 6 alkoxy group, an aromatic group or a group shown by formula: —CH 2 R 20 ;
R 3 represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 3 -C 7 cycloalkyl group, an aromatic group or a group shown by formula: —CH 2 R 30 in which R 30 represents an alkenyl group or an alkynyl group;
each of R 6 and R 7 independently represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 3 -C 7 cycloalkyl group, a C 2 -C 8 alkanoyl group, an arylalkanoyl group having carbon atoms up to 10, an aroyl group having carbon atoms up to 11, an aromatic group, or a group shown by formula: —CH 2 R 60 (in which R 60 represents a C 2 -C 6 alkenyl group or a C 2 -C 6 alkynyl group); or R 6 and R 7 are combined together to form a saturated 5- to 7-membered cyclic amino group which may contain other hetero atom(s) in the ring thereof;
R 40 represents a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group or an aromatic group;
n represents 0, 1 or 2; and,
R 20 represents a C 2 -C 6 alkenyl group or a C 2 -C 6 alkynyl group;
in which:
the substituent(s) of said substituted C 1 -C 8 alkyl group means a halogen atom, hydroxy, a C 1 -C 6 alkoxy group, cyano, a C 2 -C 8 alkanoyl group, an arylalkanoyl group having carbon atoms up to 10, an aroyl group having carbon atoms up to 11, an aromatic group, and —CONR 4 R 5 in which each of R 4 and R 5 independently represents a hydrogen atom or a C 1 -C 8 alkyl group or R 4 and R 5 are combined together to form a saturated 5- to 7-membered cyclic amino group which may contain other hetero atom(s) in the ring; —NR 6 R 7 ; or a group shown by:
in which:
E represents a nitrogen atom or a CH group and
R″ represents a hydrogen atom, a C 1 -C 8 alkyl group or a substituted C 1 -C 8 alkyl group substituted with hydroxy, a C 1 -C 6 alkoxy group, cyano, carboxyl, a C 2 -C 6 alkoxycarbonyl group, a C 2 -C 8 alkanoyl group, an arylalkanoyl group having carbon atoms up to 10, an aroyl group having carbon atoms up to 11, an aromatic group, a group shown by —NR 6 R 7 , or a group shown by —CONR 4 R 5 , in which each of R 4 and R 5 independently represents a hydrogen atom or a C 1 -C 8 alkyl group or R 4 and R 5 are combined together to form a saturated 5- to 7-membered cyclic amino group which may contain other hetero atom(s) therein; and the ring of
is a 3- to 8-membered saturated aliphatic ring or saturated hetero ring containing one nitrogen atom;
each of the aromatic groups being selected from the group consisting of (a) an aryl group having carbon atoms up to 10, (b) a 5- or 6-membered hetero-aryl group containing 1 to 4 nitrogen atom(s), (c) a 5- or 6-membered hetero-aryl group containing 1 to 2 nitrogen atom(s) and one oxygen atom or one sulfur atom, and (d) a furyl group; and,
each of the aromatic groups may be substituted with a substituent selected from the group consisting of a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a halogen atom, nitro, a C 2 -C 6 alkoxy-carbonyl group, carboxyl and a group selected from the group shown by formulae: —OR 3 , —NR 6 R 7 , —CONR 6 R 7 , —SO 2 NR 6 R 7 and —S(O) n R 40 ;
provided that said indoloylguanidine derivative does not include 1-methyl-2-indoloylguanidine; or,
a pharmaceutically acceptable acid addition salt thereof.
3. An indoloylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof according to claim 1 , wherein:
R 2 represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 3 -C 7 cycloalkyl group, hydroxy, a C 1 -C 6 alkoxy group or a group shown by formula: —CH 2 R 20 ;
R 3 represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 3 -C 7 cycloalkyl group or a group shown by formula: —CH 2 R 30 , in which R 30 represents a C 2 -C 6 alkenyl group or a C 2 -C 6 alkynyl group;
each of R 6 and R 7 independently represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 3 -C 7 cycloalkyl group or a group shown by formula: —CH 2 R 60 ; or R 6 and R 7 are combined together to form a saturated 5- to 7-membered cyclic amino group which may contain other hetero atom(s) in the ring thereof; and,
R 40 represents a C 1 -C 8 alkyl group or a substituted C 1 -C 8 alkyl group.
4. An indoloylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof according to claim 3 , wherein:
R 1 represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, C 2 -C 6 alkenyl group, a C 3 -C 7 cycloalkyl group, a halogen atom, nitro, a C 2 -C 8 alkanoyl group, carboxyl, an aryl group having carbon atoms up to 10, a C 1 -C 8 alkylsulfonyl group, or a group shown by formula: —OR 3 or —NR 6 R 7 ;
R 3 represents a hydrogen atom, a C 1 -C 8 alkyl group or a substituted C 1 -C 8 alkyl group;
each of R 6 and R 7 independently represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 2 -C 8 alkanoyl group or an aroyl group having carbon atoms up to 11; or R 6 and R 7 are combined together to form a saturated 5- to 7-membered cyclic amino group which may contain other hetero atom(s) in the ring thereof.
5. An indoloylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof according to claim 3 , wherein:
R 1 represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group (in which the substituent is hydroxy or —NR 6 R 7 ), a C 1 -C 8 polyhaloalkyl group, a C 2 -C 6 alkenyl group, a C 3 -C 7 cycloalkyl group, a halogen atom, nitro, a C 2 -C 8 alkanoyl group, carboxyl, phenyl, a C 1 -C 8 alkylsufonyl group, or a group shown by formula: —OR 3 (in which R 3 represents a hydrogen atom; a C 1 -C 8 alkyl group; or a substituted C 1 -C 8 alkyl group substituted with hydroxy, carboxyl, phenyl, —CONR 4 R 5 in which each of R 4 and R 5 independently represents a hydrogen atom or a C 1 -C 8 alkyl group, or a group shown by formula: —NR 6 R 7 .
6. An indoloylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof according to claim 3 , wherein:
R 1 represents a C 1 -C 8 alkyl group, a C 1 -C 8 polyhaloalkyl group, a C 2 -C 6 alkenyl group, a halogen atom, nitro, or a group shown by formula: —OR 3 , in which R 3 represents a hydrogen atom or a C 1 -C 8 alkyl group, or a substituted C 1 -C 8 alkyl group substituted with hydroxy, —CONR 4 R 5 in which each of R 4 and R 5 independently represents a hydrogen atom or a C 1 -C 8 alkyl group, or a group shown by formula: —NR 6 R 7 .
7. An indoloylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof according to any one of claim 3 , 4 , 5 or 6 , wherein:
R 2 represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, hydroxy or an alkoxy group.
8. An indoloylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof according to any one of claim 3 , 4 , 5 or 6 which is a 2-indoloylguanidine compound.
9. An indoloylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof, wherein said indoloylguanidine derivative is represented by general formula (2):
wherein:
each of R 8 , R 9 , R 10 , R 11 , and R 12 independently represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 2 -C 6 alkenyl group, a C 2 -C 6 alkynyl group, a C 3 -C 7 cycloalkyl group, a halogen atom, nitro, a C 2 -C 8 alkanoyl group, an arylalkanoyl group having carbon atoms up to 10, an aroyl group having carbon atoms up to 11, carboxyl, a C 2 -C 6 alkoxycarbonyl group, an aromatic group, a group shown by formula: —OR 3 , —NR 6 R 7 , —SO 2 NR 6 R 7 or —S(O) n R 40 , and a group shown by formula:
wherein A represents an oxygen atom or a group shown by formula: —S(O) n — or N(R 50 )— (in which R 50 is a hydrogen atom or a C 1 -C 8 alkyl group; R′ represents a hydrogen atom, a C 1 -C 8 alkyl group or a substituted C 1 -C 8 alkyl group); and
represents a saturated 3 to 8-membered hetero ring containing one nitrogen atom;
R 2 represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 3 -C 7 cycloalkyl group, hydroxy, a C 1 -C 6 alkoxy group, an aromatic group or a group shown by formula: —CH 2 R 20 ;
R 3 represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 3 -C 7 cycloalkyl group, an aromatic group or a group shown by formula: —CH 2 R 30 in which R 30 represents a C 2 -C 6 alkenyl group or an alkynyl group;
each of R 6 and R 7 independently represents a hydrogen atom, EL C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 3 -C 7 cycloalkyl group, a C 2 -C 8 alkanoyl group, an arylalkanoyl group having carbon atoms up to 10, an aroyl group having carbon atoms up to 11, an aromatic group, or a group shown by formula: —CH 2 R 60 (in which R 60 represents a C 2 -C 6 alkenyl group or a C 2 -C 6 alkynyl group); or R 6 and R 7 are combined together to form a saturated 5- to 7-membered cyclic amino group which may contain other hetero atoms in the ring thereof;
R 40 represents a C 1 -C 8 alkyl group or a substituted C 1 -C 8 alkyl group;
n represents 0, 1 or 2; and,
R 20 represents a C 2 -C 6 alkenyl group or a C 2 -C 6 alkynyl group;
in which:
the substituent(s) of said substituted C 1 -C 8 alkyl group means a halogen atom, hydroxy, a C 1 -C 6 alkoxy group, cyano, a C 2 -C 8 alkanoyl group, an arylalkanoyl group having carbon atoms up to 10, an aroyl group having carbon atoms up to 11, an aromatic group, or —CONR 4 R 5 in which each of R 4 and R 5 independently represents a hydrogen atom or a C 1 -C 8 alkyl group or R 4 and R 5 are combined together to form a saturated 5- to 7-membered cyclic amino group which may contain other hetero atom(s) in the ring; —NR 6 R 7 ; or a group shown by:
in which:
E represents a nitrogen atom or a CH group and
R″ represents a hydrogen atom, a C 1 -C 8 alkyl group or a substituted C 1 -C 8 alkyl group substituted with hydroxy, a C 1 -C 6 alkoxy group, cyano, carboxyl, a C 2 -C 6 alkoxycarbonyl group, a C 2 -C 8 alkanoyl group, an arylalkanoyl group having carbon atoms up to 10, an aroyl group having carbon atoms up to 11, an aromatic group, a group shown by —NR 6 R 7 , or a group shown by —CONR 4 R 5 , in which each of R 4 and R 5 independently represents a hydrogen atom or a C 1 -C 8 alkyl group or R 4 and R 5 are combined together to form a saturated 5- to 7-membered cyclic amino group which may contain other hetero atom(s) therein; and the ring of
is a 3- to 8-membered saturated aliphatic ring or saturated hetero ring containing one nitrogen atom;
each of the aromatic groups being selected from the group consisting of (a) an aryl group having carbon atoms up to 10, (b) a 5- or 6-membered hetero-aryl group containing 1 to 4 nitrogen atom(s), (c) a 5- or 6-membered hetero-aryl group containing 1 to 2 nitrogen atom(s) and one oxygen atom or one sulfur atom, and (d) a furyl group; and,
each of the aromatic groups may be substituted with a substituent selected from the group consisting of a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a halogen atom, nitro, a C 2 -C 6 alkoxy-carbonyl group, carboxyl and a group selected from the group shown by formulae: —OR 31 —NR 6 R 7 , —CONR 6 R 71 —SO 2 NR 6 R 7 and —S(O) n R 40 ;
provided that said indoloylguanidine derivative does not include 1-methyl-2-indoloylguanidine.
10. An indoloylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof according to claim 9 , wherein R 8 represents a hydrogen atom, and R 10 represents a hydrogen atom or a halogen atom.
11. An indoloylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof according to any one of claim 9 or 10 , wherein R 9 represents a hydrogen atom, a C 1 -C 8 alkyl group, a C 1 -C 8 polyhaloalkyl group, a C 3 -C 7 cycloalkyl group, a C 2 -C 8 alkenyl group, a halogen atom, nitro, a C 1 -C 8 alkylsulfonyl group or a group shown by formula: —OR 33 , in which R 33 represents a hydrogen atom or a C 1 -C 8 alkyl group or an aralkyl group.
12. An indoloylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof according to any one of claim 9 or 10 , wherein each of R 11 and R 12 independently represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, in which the substituent is hydroxy or —NR 6 R 7 , a C 1 -C 8 polyhaloalkyl group, a C 2 -C 6 alkenyl group, a C 3 -C 7 cycloalkyl group, a halogen atom, nitro, or a group shown by formula: —OR 3 or —NR 6 R 7 .
13. An indoloylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof according to any one of claim 9 or 10 , wherein R 2 represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, hydroxy or a C 1 -C 6 alkoxy group.
14. An indoloylguanidine derivative represented by general formula (3):
wherein:
the guanidinocarbonyl group may be located at any open position on either the 5-membered or 6-membered rings comprising the indole nucleus, x+xa=5 wherein x is 3 or 4 and xa is 1 or 2 such that each R 1 and each R a is located at the positions on the indole nucleus not occupied by the guanidinocarbonyl group, and each R 1 independently represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 2 -C 6 alkenyl group, a C 2 -C 6 alkynyl group, a C 3 -C 7 cycloalkyl group, a halogen atom, nitro, a C 2 -C 8 alkanoyl group, an arylalkanoyl group having carbon atoms up to 10, an aroyl group having carbon atoms up to 11, carboxyl, a C 2 -C 6 alkoxycarbonyl group, an aromatic group, a group shown by formula: —OR 3 , —NR 6 R 7 , —SO 2 NR 6 R 7 or —S(O) n R 40 , and a group shown by formula:
wherein A represents an oxygen atom or a group shown by formula: —S(O) n — or —N (R 50 )— (in which R 50 is a hydrogen atom or a C 1 -C 8 alkyl group; R′ represents a hydrogen atom, a C 1 -C 8 alkyl group or a substituted C 1 -C 8 alkyl group); and
represents a saturated 3 to 8-membered hetero ring containing one nitrogen atom;
R 2 represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 3 -C 7 cycloalkyl group, hydroxy, a C 1 -C 6 alkoxy group, a group shown by formula: —CH 2 R 20 or an aromatic group;
when R 2 is an aromatic group, R a represents R 1 ;
when R 2 is a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 3 -C 7 cycloalkyl group, hydroxy, a C 1 -C 6 alkoxy group or —CH 2 R 20 ;
R a may be one or two substituent(s), which may be the same or different and represents an aryl-C 1 -C 8 alkyl group or a hetero-aryl-C 1 -C 8 alkyl group, in which the aryl moiety in these groups contains a substituent(s) selected from the group consisting of a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 2 -C 6 alkoxycarbonyl group, carboxyl, —CONR 6 R 7 , —SO 2 NR 6 R 7 and —S(O) n R 40 ; or
R a represents a group shown by formula: —A—R b , in which A represents an oxygen atom or a group shown by formula: —S(O) n — or —N (R 50 )— (in which R 50 is a hydrogen atom or a C 1 -C 8 alkyl group); R b represents an aryl group or a hetero-aryl group in which the aryl moiety and the hetero-aryl group may contain a substituent(s) selected from the group consisting of a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a halogen atom, nitro, a C 2 -C 6 alkoxycarbonyl group, carboxyl, —OR 3 , —NR 6 R 7 , —CONR 6 R 7 , —SO 2 NR 6 R 7 and —S(O) n R 40 or,
Ra represents a group shown by formula:
wherein A represents an Oxygen atom or a group shown by formula: —S(O) n — or —N(R 50 )— (in which R 50 is a hydrogen atom or a C 1 -C 8 alkyl group); R′ represents a hydrogen atom, a C 1 -C 8 alkyl group or a substituted C 1 -C 8 alkyl group; and
represents a saturated 3 to 8-membered hetero ring containing one nitrogen atom; or,
R a represents a group shown by formula:
—A—(CH 2 ) m —R c
wherein A represents an oxygen atom or a group shown by formula: —S(O) n — or —N (R 50 )— (in which R 50 is a hydrogen atom or a C 1 -C 8 alkyl group); R c represents an aryl group or a hetero-aryl group in which the aryl moiety and the hetero-aryl group contain a substituent(s) selected from the group consisting of a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 2 -C 6 alkoxycarbonyl group, carboxyl, —CONR 6 R 7 , —OR 31 , —SO 2 NR 6 R 7 and —S(O) n R 40 ; m represents 1 to 8; and R 31 represents a substituted C 1 -C 8 alkyl group, a C 3 -C 7 cycloalkyl group or —CH 2 R 30 (in which R 30 represents a C 2 -C 6 alkenyl group or a C 2 -C 6 alkynyl group);
R 3 represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 3 -C 7 cycloalkyl group, an aromatic group or a group shown by formula: —(CH 2 R 30 in which R 30 represents a C 2 -C 6 alkenyl group or a C 2 -C 6 alkynyl group;
each of R 6 and R 7 independently represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 3 -C 7 cycloalkyl group, a C 2 -C 8 alkanoyl group, an arylalkanoyl group having carbon atoms up to 10, an aroyl group having carbon atoms up to 11, an aromatic group or a group shown by formula: —CH 2 R 60 (in which R 60 represents a C 2 -C 6 alkenyl group or a C 2 -C 6 alkynyl group); or R 6 and R 7 are combined together to form a saturated 5-to 7-membered cyclic amino group which may contain other hetero atom(s) in the ring thereof;
R 40 represents a C 1 -C 8 alkyl group or a substituted C 1 -C 8 alkyl group;
n represents 0, 1 or 2; and,
R 20 represents a C 2 -C 6 alkenyl group or a C 2 -C 6 alkynyl group;
in which:
the substituent(s) of said substituted C 1 -C 8 alkyl group means a halogen atom, hydroxy, a C 1 -C 6 alkoxy group, cyano, a C 2 -C 8 alkanoyl group, an arylalkanoyl group having carbon atoms up to 10, an aroyl group having carbon atoms up to 11, an aromatic group, and —CONR 4 R 5 in which each of R 4 and R 5 independently represents a hydrogen atom or a C 1 -C 8 alkyl group or R 4 and R 5 are combined together to form a saturated 5- to 7-membered cyclic amino group which may contain other hetero atom(s) in the ring; —NR 6 R 7 ; or a group shown by:
in which:
E represents a nitrogen atom or a CH group and
R″ represents a hydrogen atom, a C 1 -C 8 alkyl group or a substituted C 1 -C 8 alkyl group substituted with hydroxy, a C 1 -C 6 alkoxy group, cyano, carboxyl, a C 2 -C 6 alkoxycarbonyl group, a C 2 -C 8 alkanoyl group, an arylalkanoyl group having carbon atoms up to 10, an aroyl group having carbon atoms up to 11, an aromatic group, a group shown by —NR 6 R 7 , or a group shown by —CONR 4 R 5 , in which each of R 4 and R 5 independently represents a hydrogen atom or a C 1 -C 8 alkyl group or R 4 and R 5 are combined together to form a saturated 5- to 7-membered cyclic amino group which may contain other hetero atom(s) therein; and the ring of
is a 3- to 8-membered saturated aliphatic ring or saturated hetero ring containing one nitrogen atom;
each of the aromatic groups being selected from the group consisting of (a) an aryl group having carbon atoms up to 10, (b) a 5- or 6-membered hetero-aryl group containing 1 to 4 nitrogen atom(s), (c) a 5- or 6-membered hetero-aryl group containing 1 to 2 nitrogen atom(s) and one oxygen atom or one sulfur atom, and (d) a furyl group; and,
each of the aromatic groups may be substituted with a substituent selected from the group consisting of a C 1 -C 8 alkyl group, a substituted C 1-C 8 alkyl group, a halogen atom, nitro, a C 2 -C 6 alkoxy-carbonyl group, carboxyl and a group selected from the group shown by formulae: —OR 3 , —NR 6 R 7 , —CONR 6 R 7 , —SO 2 NR 6 R 7 , and —S(O) n R 40 ; or,
a pharmaceutically acceptable acid addition salt thereof.
15. An indoloylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof according to claim 14 , wherein:
R 1 represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 2 -C 6 alkenyl group, a C 2 -C 6 alkynyl group, a C 3 -C 7 cycloalkyl group, a halogen atom, nitro, a C 2 -C 8 alkanoyl group, an arylalkanoyl group having carbon atoms up to 10, an aroyl group having carbon atoms up to 11, carboxyl, a C 2 -C 6 alkoxycarbonyl group, an aromatic group, a group shown by formula: —OR 3 , —NR 6 R 7 , —SO 2 NR 6 R 7 or —S(O) n R 40 ;
R 2 represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 3 -C 7 cycloalkyl group, hydroxy, a C 1 -C 6 alkoxy group, a group shown by formula: —CH 2 R 20 or an aromatic group;
when R 2 is an aromatic group, R a represents R 1 ;
when R 2 is a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 3 -C 7 cycloalkyl group, hydroxy, a C 1 -C 6 alkoxy group or —CH 2 R 20 ;
R a represents an aryl-C 1 -C 8 alkyl group or a hetero-aryl-C 1 -C 8 alkyl group, in which the aryl moiety in these groups contains a substituent(s) selected from the group consisting of a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 2 -C 6 alkoxycarbonyl group, carboxyl, —CONR 6 R 7 , —SO 2 NR 6 R 7 and —S(O) n R 40 ; or,
R a represents a group shown by formula: —A—R b , in which A represents an oxygen atom or a group shown by formula: —S(O) n — or —N(R 50 )— (in which R 50 is a hydrogen atom or a C 1 -C 8 alkyl group); R b represents an aryl group or a hetero-aryl group in which the aryl moiety and the hetero-aryl group may contain a substituent(s) selected from the group consisting of a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a halogen atom, nitro, a C 2 -C 6 alkoxycarbonyl group, carboxyl, —OR 3 , —NR 6 R 7 , —CONR 6 R 7 , —SO 2 NR 6 R 7 and —S(O) n R 40 ; or,
R a represents a group shown by formula:
—A—(CH 2 ) m R c
wherein A represents an oxygen atom or a group shown by formula: —S(O) n — or —N (R 50 )— (in which R 50 is a hydrogen atom or a C 1 -C 8 alkyl group); R c represents an aryl group or a hetero-aryl group in which the aryl moiety and the hetero-aryl group contain a substituent(s) selected from the group consisting of a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 2 -C 6 alkoxycarbonyl group, carboxyl, —CONR 6 R 7 , —OR 31 , —SO 2 NR 6 R 7 and —S(O) n R 40 ; m represents 1 to 8; and R 31 represents a substituted C 1 -C 8 alkyl group, a C 3 -C 7 cycloalkyl group or —CH 2 R 30 (in which R 30 represents a C 2 -C 6 alkenyl group or a C 2 -C 6 alkynyl group);
R 3 represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 3 -C 7 cycloalkyl group, an aromatic group or a group shown by formula: —CH 2 R 30 in which R 30 represents a C 2 -C 6 alkenyl group or a C 2 -C 6 alkynyl group;
each of R 6 and R 7 independently represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 3 -C 7 cycloalkyl group, a C 2 -C 8 alkanoyl group, an arylalkanoyl group having carbon atoms up to 10, an aroyl group having carbon atoms up to 11, an aromatic group or a group shown by formula: —CH 2 R 60 (in which R 60 represents a C 2 -C 6 alkenyl group or a C 2 -C 6 alkynyl group); or R 6 and R 7 are combined together to form a saturated 5- to 7-membered cyclic amino group which may contain other hetero atom(s) in the ring thereof;
R 40 represents a C 1 -C 8 alkyl group or a substituted C 1 -C 8 alkyl group;
n represents 0, 1 or 2; and,
R 20 represents a C 2 -C 6 alkenyl group or a C 2 -C 6 alkynyl group;
in which:
the substituent(s) of said substituted C 1 -C 8 alkyl group means a halogen atom, hydroxy, a C 1 -C 6 alkoxy group, cyano, carboxyl, a C 2 -C 6 alkoxycarbonyl group, a C 2 -C 8 alkanoyl group, an arylalkanoyl group having carbon atoms up to 10, an aroyl group having carbon atoms up to 11, an aromatic group, and —CONR 4 R 5 in which each of R 4 and R 5 independently represents a hydrogen atom or a C 1 -C 8 alkyl group or R 4 and R 5 are combined together to form a saturated 5- to 7-membered cyclic amino group which may contain other hetero atom(s) in the ring; —NR 6 R 7 ; or a group shown by:
in which:
E represents a nitrogen atom or a CH group and
R″ represents a hydrogen atom, a C 1 -C 8 alkyl group or a substituted C 1 -C 8 alkyl group substituted with hydroxy, a C 1 -C 6 alkoxy group, cyano, carboxyl, a C 2 -C 6 alkoxycarbonyl group, a C 2 -C 8 alkanoyl group, an arylalkanoyl group having carbon atoms up to 10, an aroyl group having carbon atoms up to 11, an aromatic group, a group shown by —NR 6 R 7 , or a group shown by —CONR 4 R 5 , in which each of R 4 and R 5 independently represents a hydrogen atom or a C 1 -C 8 alkyl group or R 4 and R 5 are combined together to form a saturated 5- to 7-membered cyclic amino group which may contain other hetero atom(s) therein; and the ring of
is a 3- to 8-membered saturated aliphatic ring or saturated hetero ring containing one nitrogen atom;
each of the aromatic groups being selected from the group consisting of (a) an aryl group having carbon atoms up to 10, (b) a 5- or 6-membered hetero-aryl group containing 1 to 4 nitrogen atom(s), (c) a 5- or 6-membered hetero-aryl group containing 1 to 2 nitrogen atom(s) and one oxygen atom or one sulfur atom, and (d) a furyl group; and,
each of the aromatic groups may be substituted with a substituent selected from the group consisting of a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a halogen atom, nitro, a C 2 -C 6 alkoxy-carbonyl group, carboxyl and a group selected from the group shown by formulae: —OR 3 , —NR 6 R 7 , —CONR 6 R 7 , —SO 2 NR 6 R 7 and —S(O) n R 40 .
16. An indoloylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof according to claim 14 , wherein:
R 1 represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 2 -C 6 alkenyl group, a C 2 -C 6 alkynyl group, a C 3 -C 7 cycloalkyl group, a halogen atom, nitro, a C 2 -C 8 alkanoyl group, an arylalkanoyl group having carbon atoms up to 10, an aroyl group having carbon atoms up to 11, carboxyl, a C 2 -C 6 alkoxycarbonyl group, an aromatic group, a group shown by formula: —OR 3 , —NR 6 R 7 , —SO 2 NR 6 R 7 or —S(O) n R 40 ;
R 2 represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 3 -C 7 cycloalkyl group, hydroxy, a C 1 -C 6 alkoxy group or a group shown by formula: —CH 2 R 20 ;
R a represents aralkyl group(s) or hetero-aralkyl group(s), in which the aryl moiety in these groups contains a substituent(s) selected from the group consisting of a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 2 -C 6 alkoxycarbonyl group, carboxyl, —CONR 6 R 7 , —SO 2 NR 6 R 7 and —S(O) n R 40 ; or,
R a represents a group shown by formula: —A—R b , in which A represents an oxygen atom or a group shown by formula: —S(O) n — or —N(R 50 )— (in which R 50 is a hydrogen atom or a C 1 -C 8 alkyl group); R b represents an aryl group or a hetero-aryl group in which the aryl moiety and the hetero-aryl group may contain a substituent(s) selected from the group consisting of a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a halogen atom, nitro, a C 2 -C 6 alkoxycarbonyl group, carboxyl, —OR 3 , —NR 6 R 7 , —CONR 6 R 7 , —SO 2 NR 6 R 7 and —S(O) n R 40 ;
R 3 represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 3 -C 7 cycloalkyl group or a group shown by formula: —CH 2 R 30 in which R 30 represents a C 2 -C 6 alkenyl group or a C 2 -C 6 alkynyl group;
each of R 6 and R 7 independently represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 3 -C 7 cycloalkyl group, a C 2 -C 8 alkanoyl group, an arylalkanoyl group having carbon atoms up to 10, an aroyl group having carbon atoms up to 11, or a group shown by formula: —CH 2 R 60 (in which R 60 represents a C 2 -C 6 alkenyl group or a C 2 -C 6 alkynyl group); or R 6 and R 7 are combined together to form a saturated 5- to 7-membered cyclic amino group which may contain other hetero atom(s) in the ring thereof;
R 40 represents a C 1 -C 8 alkyl group or a substituted C 1 -C 8 alkyl group;
n represents 0, 1 or 2; and,
R 20 represents a C 2 -C 6 alkenyl group or a C 2 -C 6 alkynyl group.
17. An indoloylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof, wherein said indoloylguanidine derivative is represented by general formula (2):
wherein:
R 2 represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 3 -C 7 cycloalkyl group, hydroxy, a C 1 -C 6 alkoxy group or a group shown by formula: —CH 2 R 20 ;
each of R 8 , R 9 , R 10 , R 11 and R 12 independently represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 2 -C 6 alkenyl group, a C 2 -C 6 alkynyl group, a C 3 -C 7 cycloalkyl group, a halogen atom, nitro, a C 2 -C 8 alkanoyl group, an arylalkanoyl group having carbon atoms up to 10, an aroyl group having carbon atoms up to 11, carboxyl, a C 2 -C 6 alkoxycarbonyl group, an aromatic group, or a group shown by formula: —OR 3 , —NR 6 R 7 , —SO 2 NR 6 R 7 , —S(O) n R 40 or R a but at least one of R 8 , R 9 , R 10 , R 11 and R 12 is a group shown by R a ,
R a may be one or two of R 8 , R 9 , R 10 , R 11 and R 12 , which may be the same or different and represents an aryl-C 1 -C 8 alkyl group or a hetero-aryl-C 1 -C 8 alkyl group, in which the aryl moiety in these groups contains a substituent(s) selected from the group consisting of a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 2 -C 6 alkoxycarbonyl group, carboxyl, —CONR 6 R 7 , —SO 2 NR 6 R 7 and —S(O)R 40 ; or,
R a represents a group shown by formula: —A—R b , in which A represents an oxygen atom or a group shown by formula: —S(O) n — or —N(R 50 )— (in which R 50 is a hydrogen atom or a C 1 -C 8 alkyl group); R b represents an aryl group or a hetero-aryl group in which the aryl moiety and the hetero-aryl group may contain a substituent(s) selected from the group consisting of a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a halogen atom, nitro, a C 2 -C 6 alkoxycarbonyl group, carboxyl, —OR 3 —NR 6 R 7 , —CONR 6 R 7 —SO 2 NR 6 R 7 and —S(O)R 4 ; or,
R a represents a group shown by formula:
wherein A represents an oxygen atom or a group shown by formula: —S(O) n — or —N (R 50 )— (in which R 50 is a hydrogen atom or a C 1 -C 8 alkyl group); R′ represents a hydrogen atom, a C 1 -C 8 alkyl group or a substituted C 1 -C 8 alkyl group; and
represents a saturated 3 to 8-membered hetero ring containing one nitrogen atom; or,
R a represents a group shown by formula:
—A—(CH 2 ) m —R c
wherein A represents an oxygen atom or a group shown by formula: —S(O) n — or —N (R 50 )— (in which R 50 is a hydrogen atom or a C 1 -C 8 alkyl group); R c represents an aryl group or a hetero-aryl group in which the aryl moiety and the hetero-aryl group contain a substituent(s) selected from the group consisting of a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 1 -C 8 alkoxcycarbonyl group, carboxyl, —CONR 6 R 7 , —OR 31 , —SO 2 NR 6 R 7 and —S(O) n R 40 ; m represents 1 to 8; and R 31 represents a substituted C 1 -C 8 alkyl group, a C 3 -C 7 cycloalkyl group or —CH 2 R 30 (in which R 30 represents a C 2 -C 6 alkenyl group or a C 2 -C 6 alkynyl group);
R 3 represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 3 -C 7 cycloalkyl group, an aromatic group or a group shown by formula: —CH 2 R 30 in which R 30 represents a C 2 -C 6 alkenyl group or a C 2 -C 6 alkynyl group;
each of R 6 and R 7 independently represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 3 -C 7 cycloalkyl group, a C 2 -C 8 alkanoyl group, an arylalkanoyl group having carbon atoms up to 10, an aroyl group having carbon atoms up to 11, an aromatic group or a group shown by formula: —CH 2 R 60 (in which R 60 represents a C 2 -C 6 alkenyl group or a C 2 -C 6 alkynyl group); or R 6 and R 7 are combined together to form a saturated 5- to 7-membered cyclic amino group which may contain other hetero atom(s) in the ring thereof;
R 40 represents a C 1 -C 8 alkyl group or a substituted C 1 -C 8 alkyl group;
n represents 0, 1 or 2; and,
R 20 represents a C 2 -C 6 alkenyl group or a C 2 -C 6 alkynyl group;
in which:
the substituent(s) of said substituted C 1 -C 8 alkyl group means a halogen atom, hydroxy, a C 1 -C 6 alkoxy group, cyano, a C 2 -C 8 alkanoyl group, an arylalkanoyl group having carbon atoms up to 10, an aroyl group having carbon atoms up to 11, an aromatic group, and —CONR 4 R 5 in which each of R 4 and R 5 independently represents a hydrogen atom or a C 1 -C 8 alkyl group or R 4 and R 5 are combined together to form a saturated 5- to 7-membered cyclic amino group which may contain other hetero atom(s) in the ring; —NR 6 R 7 ; or a group shown by:
in which:
E represents a nitrogen atom or a CH group and
R′ represents a hydrogen atom, a C 1 -C 8 alkyl grout or a substituted C 1 -C 8 alkyl group substituted with hydroxy, a C 1 -C 6 alkoxy group, cyano, carboxyl, a C 2 -C 6 alkoxycarbonyl group, a C 2 -C 8 alkanoyl group, an arylalkanoyl group having carbon atoms up to 10, an aroyl group having carbon atoms up to 11, an aromatic group, a group shown by —NR 6 R 7 , or a group shown by —CONR 4 R 5 , in which each of R 4 and R 5 independently represents a hydrogen atom or a C 1 -C 8 alkyl group or R 4 and R 5 are combined together to form a saturated 5- to 7-membered cyclic amino group which may contain other hetero atom(s) therein; and the ring of
is a 3- to 8-membered saturated aliphatic ring or saturated hetero ring containing one nitrogen atom;
each of the aromatic groups being selected from the group consisting of (a) an aryl group having carbon atoms up to 10, (b) a 5- or 6-membered hetero-aryl group containing 1 to 4 nitrogen atom(s), (c) a 5- or 6-membered hetero-aryl group containing 1 to 2 nitrogen atom(s) and one oxygen atom or one sulfur atom, and (d) a furyl group; and,
each of the aromatic groups may be substituted with a substituent selected from the group consisting of a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a halogen atom, nitro, a C 2 -C 6 alkoxy-carbonyl group, carboxyl and a group selected from the group shown by formulae: —OR 3 , —NR 6 R 7 , —CONR 6 R 7 , —SO 2 NR 6 R 7 and —S(O) n R 40 .
18. An indoloylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof according to claim 17 , wherein R 8 represents a hydrogen atom; R 9 represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 2 -C 6 alkenyl group, a C 2 -C 6 alkynyl group, a C 3 -C 7 cycloalkyl group, a halogen atom, nitro, a C 2 -C 8 alkanoyl group, an arylalkanoyl group having carbon atoms up to 10, an aroyl group having carbon atoms up to 11, carboxyl, a C 2 -C 6 alkoxycarbonyl or a group shown by formula: —OR 3 , —NR 6 R 7 , —SO 2 NR 6 R 7 or —S(O) n R 40 ; and each of R 10 , R 11 and R 12 independently represents a hydrogen atom or a group shown by R a .
19. An indoloylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof according to claim 18 , wherein R 10 represents a hydrogen atom, and each of R 11 and R 12 independently represents a hydrogen atom or a group shown by R a .
20. An indoloylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof according to claim 19 , wherein R 9 represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a halogen atom, nitro or a group shown by formula: —OR 3 .
21. An indoloylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof according to claim 20 , wherein R a represents an aralkyl group which may contain a substituent(s) selected from the group consisting of a C 1 -C 8 alkyl group, a halogen atom, nitro, a substituted C 1 -C 8 alkyl group, C 2 -C 6 alkoxycarbonyl group, carboxyl, —NR 6 R 1 , —CONR 6 R 7 , —OR 3 , —SO 2 NR 6 R 7 and —S(O) n R 40 ; or R a represents a group shown by formula: —A—R b , in which A represents an oxygen atom or a group shown by formula: —S(O) n — or —N (R 50 )—; R b represents an aryl group which may contain a substituent(s) selected from the group consisting of a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 2 -C 6 alkoxycarbonyl group, carboxyl, —CONR 6 R 7 , —SO 2 NR 6 R 7 and —S(O) n R 40 .
22. An indoloylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof according to claim 1 , which is any one of Compounds (1) through (8) below:
(1) 7-[4-(aminomethyl)phenoxy]-4-chloro-1-methyl-2-indoloylguanidine
(2) 7-[4-(aminomethyl)benzyloxy]-4-chloro-1-methyl-2-indoloylguanidine
(3) 6-[4-(aminomethyl)benzyloxy]-4-chloro-1-methyl-2-indoloylguanidine
(4) 6-[4-(aminomethyl)phenoxy]-4-chloro-1-methyl-2-indoloylguanidine
(5) 4-chloro-6-[4-(dimethylaminomethyl)phenoxy]-1-methyl-2-indoloylguanidine
(6) 4-chloro-7-[4-(dimethylaminomethyl)phenoxy]-1-methyl-2-indoloylguanidine
(7) 4-chloro-7-[4-(dimethylaminomethyl)benzyloxy]-1-methyl-2-indoloylguanidine
(8) 4-chloro-6-[4-(dimethylaminomethyl)benzyloxy]-1-methyl-2-indoloylguanidine.
23. An indoloylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof according to claim 14 , which is represented by general formula (3):
wherein:
the guanidinocarbonyl group may be located at any open position on either the 5-membered or 6-membered rings comprising the indole nucleus, x+xa=5 wherein x is 3 or 4 and xa is 1 or 2 such that each R 1 and each Ra is located at the positions on the indole nucleus not occupied by the guanidinocarbonyl group, and each R 1 independently represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 2 -C 6 alkenyl group, a C 2 -C 6 alkynyl group, a C 3 -C 7 cycloalkyl group, a halogen atom, nitro, a C 2 -C 8 alkanoyl group, an arylalkanoyl group having carbon atoms up to 10, an aroyl group having carbon atoms up to 11, carboxyl, a C 2 -C 6 alkoxycarbonyl group, an aromatic group, a group shown by formula: —OR 3 , —NR 6 R 7 , —SO 2 NR 6 R 7 or —S(O) n R 40 ;
R 2 represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 3 -C 7 cycloalkyl group, hydroxy, a C 1 -C 6 alkoxy group, a group shown by formula: —CH 2 R 20 or an aromatic group;
R a contains one or two substituent(s), which may be the same or different and represents an aryl-C 1 -C 8 alkyl group or a hetero-aryl-C 1 -C 8 alkyl group, in which the aryl moiety in these groups contains a substituent(s) selected from the group consisting of a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a
C 2 -C 6 alkoxycarbonyl group, carboxyl, —CONR 6 R 7 and —SO 2 NR 6 R 7 ; or,
R a represents a group shown by formula: —A—R b , in which A represents an oxygen atom or a group shown by formula: —S(O) n — or —N(R 50 )— (in which R 50 is a hydrogen atom or a C 1 -C 8 alkyl group); R b represents an aryl group or a hetero-aryl group in which the aryl moiety and the hetero-aryl group contain a substituent(s) selected from the group consisting of a C 1 -C 8 alkyl group, a C 1 -C 8 alkyl group substituted with —NR 6 R 7 , a halogen atom, nitro, a C 2 -C 6 alkoxycarbonyl group, carboxyl, —OR 3 , —NR 6 R 7 , —CONR 6 R 7 and —SO 2 NR 6 R 7 or,
R a represents a group shown by formula:
—A—(CH 2 ) m —R c
wherein A represents an oxygen atom or a group shown by formula: —S(O) n — or —N (R 50 )— (in which R 50 is a hydrogen atom or a C 1 -C 8 alkyl group); R c represents an aryl group or a hetero-aryl group in which the aryl moiety and the hetero-aryl group contain a substituent(s) selected from the group consisting of a C 1 -C 8 alkyl group, a C 1 -C 8 alkyl group substituted with —NR 6 R 7 , a C 2 -C 6 alkoxycarbonyl group, carboxyl, —CONR 6 R 7 —, —OR 3 , and —SO 2 NR 6 R 7 ; m represents 1 to 8; and, R 31 represents a substituted C 1 -C 8 alkyl group, a C 3 -C 7 cycloalkyl group or —CH 2 R 30 (in which R 3 ( 1 represents a C 2 -C 6 alkenyl group or a C 2 -C 6 alkynyl group);
R 3 represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 3 -C 7 cycloalkyl group or a group shown by formula: —CH 2 R 30 in which R 30 represents a C 2 -C 6 alkenyl group or a C 2 -C 6 alkynyl group;
each of R 6 and R 7 independently represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, a C 3 -C 7 cycloalkyl group, a C 2 -C 8 alkanoyl group, an arylalkanoyl group having carbon atoms up to 10, an aroyl group having carbon atoms up to 11, or a group shown by formula: —CH 2 R 60 (in which R 60 represents a C 2 -C 6 alkenyl group or a C 2 -C 6 alkynyl group); or R 6 and R 7 are combined together to form a saturated 5- to 7-membered cyclic amino group which may contain other hetero atom(s) in the ring thereof;
R 40 represents a C 1 -C 8 alkyl group or a substituted C 1 -C 8 alkyl group;
n represents 0, 1 or 2; and,
R 20 represents a C 2 -C 6 alkenyl group or a C 2 -C 6 alkynyl group.
24. An indoloylguanidine derivative represented by formula (1):
wherein:
the guanidinocarbonyl group may be located at any open position on either the 5-membered or 6-membered rings comprising the indole nucleus, x=5 so that R 1 is located at each position on the indole nucleus not occupied by the guanidinocarbonyl group, and each R 1 independently represents
a hydrogen atom,
a C 1 -C 8 alkyl group,
an substituted C 1 -C 8 alkyl group in which the substituent means a cycloalkyl group having 3 to 7 carbon atoms, a halogen atom, hydroxy, an alkoxy group having carbon atoms up to 6, cyano, an alkanoyl group having carbon atom up to 8, an aryl group having carbon atoms up to 10 which may be substituted with hydroxy, an alkoxy group having carbon atoms up to 6, a halogen atom, nitro or a group shown by formula:
—NR 6 R 7 ; a 5 or 6-membered heteroaryl group containing 1 to 4 nitrogen atoms which may be substituted with hydroxy, an alkoxy group having carbon atoms up to 6, a halogen atom, nitro or a group shown by formula: —NR 6 R 7 ; a 5 or 6-membered heteroaryl group containing 1 to 2 nitrogen atoms and one oxygen atom or one sulfur atom which may be substituted with hydroxy, an alkoxy group having carbon atoms up to 6, a halogen atom, nitro or a group shown by formula: —NR 6 R 7 ; 2-furyl, 3-furyl, 2-thienyl, 3-thienyl or a group shown by formula: —CONR 4 R 5 or —NR 6 R 7 ,
an alkenyl group having carbon atoms up to 6,
an alkynyl group having 2 to 4 carbon atoms,
a cycloalkyl group having 3 to 7 carbon atoms,
a halogen atom,
a nitro group,
an alkanoyl group having carbon atoms up to 8,
an arylalkanoyl group having carbon atoms up to 10, an aroyl group having carbon atoms up to 11,
a carboxyl group,
an alkoxycarbonyl group having carbon atoms up to 6,
an aryl group having carbon atoms up to 10 which may be substituted with hydroxy, an alkoxy group having carbon atoms up to 6, a halogen atom, nitro or a group shown by formula: —NR 6 R 7 ;
a 5 or 6-membered heteroaryl group containing 1 to 4 nitrogen atoms which may be substituted with hydroxy, an alkoxy group having carbon atoms up to 6, a halogen atom, nitro or a group shown by formula: —NR 6 R 7 ;
a 5 or 6-membered hetoroaryl group containing 1 to 2 nitrogen atoms and one oxygen atom or one sulfur atom which may be substituted with hydroxy, an alkoxy group having carbon atoms up to 6, a halogen atom, nitro or a group shown by formula: —NR 6 R 7 ; 2-furyl, 3-furyl, 2-thienyl, 3-thienyl or
a group shown by formula: —OR 3 , —NR 6 R 7 , —SO 2 NR 6 R 7 or —S(O) n R 40 ;
R 2 represents
a hydrogen atom,
an alkyl group having carbon atoms up to 8,
a substituted C 1 -C 8 alkyl group as defined above,
a cycloalkyl group having 3 to 7 carbon atoms,
a hydroxy group,
an alkoxy group having carbon atoms up to 6, or
a group shown by formula: —CH 2 R 20 ;
R 3 represents
a hydrogen atom,
an alkyl group having carbon atoms up to 8,
a substituted C 1 -C 8 alkyl group as defined above,
a cycloalkyl group having 3 to 7 carbon atoms, or
a group shown by formula: —CH 2 R 30 , wherein R 30 represents an alkenyl group having carbon atoms up to 6, or an alkynyl group having 2 to 6 carbon atoms;
each of R 4 and R 5 independently represents hydrogen atom or an alkyl group having carbon atoms up to 8, or R 4 and R 5 are combined together to form a saturated 5- to 7-membered cyclic group containing 1 to 3 nitrogen atoms and a saturated 5- to 7-membered cyclic group containing one nitrogen atom and one oxygen atom;
each of R 6 and R 7 independently represents
a hydrogen atom,
an alkyl group having carbon atoms up to 8,
a substituted C 1 -C 8 alkyl group in which the substituent means a cycloalkyl group having 3 to 7 carbon atoms, hydroxy, an alkoxy group having carbon atoms up to 6, carboxyl, an alkoxycarbonyl group having carbon atoms up to 6, an alkanoyl group having carbon atom up to 8, an aryl group having carbon atoms up to 10 or a group shown by formula: —CONR 4 R 5 or —NR 4 R 5 ,
a cycloalkyl group having 3 to 7 carbon atoms,
an alkanoyl group having carbon atoms up to 8,
an arylalkanoyl group having carbon atoms up to 10,
an aroyl group having carbon atoms up to 11,
a group shown by formula: —CH 2 R 60 , wherein R 60 represents an alkenyl group having carbon atoms up to 6, or an alkynyl group having 2 to 6 carbon atoms, or
R 6 and R 7 are combined together to form a saturated 5- to 7-membered cyclic group containing 1 to 3 nitrogen atoms or a saturated 5- to 7-membered cyclic group containing one nitrogen atom and one oxygen atom;
R 40 represents an alkyl group having carbon atoms up to 8, or a substituted C 1 -C 8 alkyl group as defined above,
n represents 0, 1 or 2; and,
R 20 represents an alkenyl group having carbon atoms up to 6 or an alkynyl group having 2 to 6 carbon atoms;
provided that said indoloylguanidine derivative does not include 1-methyl-2-indoloylguanidine;
or, a pharmaceutically acceptable acid addition salt thereof.
25. An indoloylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof according to claim 24 , wherein:
R 1 represents
a hydrogen atom,
an alkyl group having carbon atoms up to 8,
a substituted C 1 -C 8 alkyl group as defined above
an alkenyl group having carbon atoms up to 6, a cycloalkyl group having 3 to 7 carbon atoms,
a halogen atom,
a nitro group,
an alkanoyl group having carbon atoms up to 8,
carboxyl group,
an aryl group having carbon atoms up to 10,
an alkyl sulfonyl group having carbon atoms up to 8, or
a group shown by formula: —OR 3 or —NR 6 R 7 ;
R 3 represents
a hydrogen atom,
an alkyl group having carbon atoms up to 8, or
a substituted C 1 -C 8 alkyl group as defined above
each of R 6 and R 7 independently represents
a hydrogen atom,
an alkyl group having carbon atoms up to 8 in which the substituent means a cycloalkyl group having 3 to 7 carbon atoms, hydroxy, an alkoxy group having carbon atoms up to 6, carboxyl, an alkoxycarbonyl group having carbon atoms up to 6, an alkanoyl group having carbon atom up to 8, an aryl group having carbon atoms up to 10 or a group shown by formula: —CONR 4 R 5 or —NR 6 R 7 ,
an alkanoyl group having carbon atoms up to 8, or
an aroyl group having carbon atoms up to 11; or
R 6 and R 7 are combined together to form a saturated 5- to 7-membered cyclic group containing 1 to 3 nitrogen atoms or a saturated 5- to 7-membered cyclic group containing one nitrogen atom and one oxygen atom.
26. An indoloylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof according to claim 24 , wherein R 1 represents a hydrogen atom, an alkyl group having carbon atoms up to 8, a substituted C 1 -C 8 alkyl group wherein the substituent is a hydroxy group or a group shown by —NR 6 R 7 , a polyhalo-alkyl group having 1 to 5 carbon atoms, an alkenyl group having carbon atoms up to 6, a cycloalkyl group having 3 to 7 carbon atoms, a halogen atom, a nitro group, an alkanoyl group having carbon atoms up to 8, a carboxyl group, a phenyl group, an C 1 -C 8 alkylsulfonyl group or a group shown by formula —OR 3 wherein R 3 represents a hydrogen atom or an alkyl group having carbon atoms up to 8, or an C 1 -C 8 alkyl group substituted with a hydroxy group, a carboxyl group, a phenyl group, —CONR 4 R 5 in which each of R 4 and R 5 independently represents a hydrogen atom or an alkyl group having carbon atoms up to 8 or a group shown by formula: —NR 6 R 7 .
27. An indoloylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof according to claim 24 , wherein R 1 represents an alkyl group having carbon atoms up to 8, a polyhaloalkyl group having 1 to 5 carbon atoms, an alkenyl group having carbon atoms up to 6, a halogen atom, a nitro group or a group shown by formula OR 32 wherein R 3 represents a hydrogen atom or an alkyl group having carbon atoms up to 8, or an C 1 -C 8 alkyl group substituted with a hydroxy group, —CONR 4 R 5 in which each of R 4 and R 5 independently represents a hydrogen atom or an alkyl group having carbon atoms up to 8 or a group shown by formula: —NR 6 R 7 .
28. An indoloylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof according to any one of claim 24 , 25 , 26 or 27 , wherein R 2 represents
a hydrogen atom,
an alkyl group having carbon atoms up to 8,
a substituted C 1 -C 8 alkyl group as defined above
a hydroxy group, or
an alkoxy group having carbon atoms up to 6.
29. An indoloylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof according to any one of claim 24 , 25 , 26 or 27 , which is a 2-indoloylguanidine compound.
30. An indoloylguanidine derivative represented by formula (2):
wherein:
each of R 8 , R 9 , R 10 , R 11 and R 12 independently represents
a hydrogen atom,
an alkyl group having carbon atoms up to 8,
a substituted C 1 -C 8 alkyl group in which the substituent means a cycloalkyl group having 3 to 7 carbon atoms, a halogen atom, hydroxy, an alkoxy group having carbon atoms up to 6, cyano, an alkanoyl group having carbon atom up to 8, an aryl group having carbon atoms up to 10 which may be substituted with hydroxy, an alkoxy group having carbon atoms up to 6, a halogen atom, nitro or a group shown by formula:
—NR 6 R 7 ; a 5 or 6-membered heteroaryl group containing 1 to 4 nitrogen atoms which may be substituted with hydroxy, an alkoxy group having carbon atoms up to 6, a halogen atom, nitro or a group shown by formula: —NR 6 R 7 ; a 5 or 6-membered hetoroaryl group containing 1 to 2 nitrogen atoms and one oxygen atom or one sulfur atom which may be substituted with hydroxy, an alkoxy group having carbon atoms up to 6, a halogen atom, nitro or a group shown by formula: —NR 6 R 7 ; 2-furyl, 3-furyl, 2-thienyl, 3-thienyl or a group shown by formula: —CONR 4 R 5 or —NR 6 R 7 ,
an alkenyl group having carbon atoms up to 6,
an alkynyl group having 2 to 6 carbon atoms,
a cycloalkyl group having 3 to 7 carbon atoms,
a halogen atom,
a nitro group,
an alkanoyl group having carbon atoms up to 8,
an arylalkanoyl group having carbon atoms up to 10,
an aroyl group having carbon atoms up to 11,
a carboxyl group,
an alkoxycarbonyl group having carbon atoms up to 6,
an aryl group having carbon atoms up to 10 which may be substituted with hydroxy, an alkoxy group having carbon atoms up to 6, a halogen atom, nitro and a group shown by formula: —NR 6 R 7 ;
a 5 or 6-membered heteroaryl group containing 1 to 4 nitrogen atoms which may be substituted with hydroxy, an alkoxy group; having carbon atoms up to 6, a halogen atom, nitro or a group shown by formula: —NR 6 R 7 ;
a 5 or 6-membered hetoroaryl group containing 1 to 2 nitrogen atoms and one oxygen atom or one sulfur atom which may be substituted with hydroxy, an alkoxy group having carbon atoms up to 6, a halogen atom, nitro or a group shown by formula: —NR 6 R 7 ; 2-furyl, 3-furyl, 2-thienyl, 3-thienyl
or a group shown by formula: OR 3 , —NR 6 R 7 , —SO 2 NR 6 R 7 or —S(O) n R 40 ;
R 2 represents
a hydrogen atom,
an alkyl group; having carbon atoms up to 8,
a substituted C 1 -C 8 alkyl group as defined above,
a cycloalkyl group having 3 to 7 carbon atoms,
a hydroxy group,
an alkoxy group having carbon atoms up to 6, or
a group shown by formula: —CH 2 R 20 ;
R 3 represents
a hydrogen atom,
an alkyl group having carbon atoms up to 8,
a substituted C 1 -C 8 alkyl group as defined above,
a cycloalkyl group having 3 to 7 carbon atoms, or
a group shown by formula: —CH 2 R 30 , wherein R 30 represents an alkenyl group having carbon atoms up to 6, or an alkynyl group having 2 to 6 carbon atoms;
each of R 4 and R 5 independently represents hydrogen atom or an alkyl group having carbon atoms up to 8, or R 4 and R 5 are combined together to form a saturated 5- to 7-membered cyclic group containing 1 to 3 nitrogen atoms and a saturated 5- to 7-membered cyclic group containing one nitrogen atom and one oxygen atom;
each of R 6 and R 7 independently represents a hydrogen atom,
an alkyl group having carbon atoms up to 8,
a substituted C 1 -C 8 alkyl group in which the substituent means a cycloalkyl group having 3 to 7 carbon atoms, hydroxy, an alkoxy group having carbon atoms up to 6, carboxyl, an alkoxycarbonyl group having carbon atoms up to 6, or an alkanoyl group having carbon atom up to 8, an aryl group having carbon atoms up to 10,
a cycloalkyl group having 3 to 7 carbon atoms,
an alkanoyl group having carbon atoms up to 8, an arylalkanoyl group having carbon atoms up to 10, or an aroyl group having carbon atoms up to 11, or
a group shown by formula: —CH 2 R 60 , wherein R 60 represents an alkenyl group having carbon atoms up to 6 or an alkynyl group having 2 to 6 carbon atoms; or
R 6 and R 7 are combined together to form a saturated 5- to 7-membered cyclic group containing 1 to 3 nitrogen atoms or a saturated 5- to 7-membered cyclic group containing one nitrogen atom and one oxygen atom;
R 40 represents an alkyl group having carbon atoms up to 8, or a substituted C 1 -C 8 alkyl group as defined above,
n represents 0, 1 or 2; and,
R 20 represents an alkenyl group having carbon atoms up to 6 or an alkynyl group having 2 to 6 carbon atoms;
provided that said indoloylguanidine derivative does not include 1-methyl-2-indoloylguanidine; or,
a pharmaceutically acceptable acid addition salt thereof.
31. An indoloylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof according to claim 30 , wherein R 8 represents a hydrogen atom, and R 10 represents a hydrogen atom or a halogen atom.
32. An indoloylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof according to claim 30 or 31 , wherein R 8 represents
a hydrogen atom,
an alkyl group having up to 8 carbon atoms,
a polyhaloalkyl group having 1 to 5 carbon atoms,
a cycloalkyl group having 3 to 7 carbon atoms,
an alkenyl group having up to 6 carbon atoms,
a halogen atom,
a nitro group,
a C 1 -C 8 alkylsulfonyl group or
a group shown by formula: —OR 33 wherein R 33 represents
a hydrogen atom,
an alkyl group having up to 8 carbon atoms, or
a C 1 -C 8 alkyl group substituted with an aryl group having up to 10 carbon atoms,
which may be substituted with a hydroxy group, an alkoxy group having up to 6 carbon atoms, a halogen atom, a nitro group or a group of formula —NR 6 R 7 .
33. An indoloylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof according to claim 30 or 31 , wherein each of R 11 and R 12 independently represents
a hydrogen atom,
an alkyl group having up to 8 carbon atoms,
a substituted C 1 -C 8 alkyl group wherein the substituent is a hydroxy group or —NR 6 R 7 ,
a polyhaloalkyl group having up to 8 carbon atoms,
an alkenyl group having up to 6 carbon atoms,
a cycloalkyl group having 3 to 7 carbon atoms,
a halogen atom,
a nitro group,
—OR 3 or
—NR 6 R 7 .
34. An indoloylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof according to any one of claim 30 or 31 , wherein R 2 represents
a hydrogen atom,
an alkyl group having carbon atoms up to 8,
a substituted C 1 -C 8 alkyl group
a hydroxy group,
or an alkoxy group having carbon atoms up to 6.
35. An indolylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof according to claim 1 , wherein:
R 1 represents
a hydrogen atom,
an alkyl group having carbon atoms up to 8,
a cycloalkyl group having 3 to 7 carbon atoms,
a halogen atom,
a nitro group, and
a group shown by formula: —OR 3 , or —NR 6 R 7 ,
R 2 represents
a hydrogen atom,
an alkyl group having carbon atoms up to 8,
a substituted C 1 -C 8 alkyl group in which the substituent means hydroxy, cyano, an aryl group having carbon atoms up to 10 or carbamoyl,
R 3 represents
a hydrogen atom,
an alkyl group having carbon atoms up to 8,
a substituted C 1 -C 8 alkyl group in which the substituent means a cycloalkyl group having 3 to 7 carbon atoms, an aryl group having carbon atoms up to 10, a 5 or 6-membered heteroaryl group containing 1 to 4 nitrogen atoms, a 5 or 6-membered heteroaryl group containing 1 to 2 nitrogen atoms and one oxygen atom or one sulfur atom,
a cycloalkyl group having 3 to 7 carbon atoms or
a group shown by formula: —CH 2 R 30 , wherein R 30 represents an alkenyl group having carbon atoms up to 6, or an alkynyl group having 2 to 6 carbon atoms;
each of R 6 and R 7 independently represents
a hydrogen atom,
an alkyl group having carbon atoms up to 8,
a substituted C 1 -C 8 alkyl group in which the substituent means a cycloalkyl group having 3 to 7 carbon atoms, an aryl group having carbon atoms up to 10, a 5 or 6 membered heteroaryl group containing 1 to 4 nitrogen atoms, a 5 or 6-membered heteroaryl group containing 1 to 2 nitrogen atoms and one oxygen atom or one sulfur atom,
a cycloalkyl group having 3 to 7 carbon atoms,
a group shown by formula: —CH 2 R 60 , wherein R 60 represents an alkenyl group having carbon atoms up to 6, or an alkynyl group having 2 to 6 carbon atoms, or
R 6 and R 7 are combined together to form a saturated 5- to 7-membered cyclic group containing 1 to 3 nitrogen atoms or a saturated 5- to 7-membered cyclic group containing one nitrogen atom and one oxygen atom.
36. An indoloylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof according to any one of claim 1 , 2 , 14 , 24 , or 30 , wherein the derivative is
37. An indoloylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof, which is selected from the group consisting of 1-methyl-2-indoloylguanidine and 1,4-dimethyl-2-indoloylguanidine.
38. An indoloylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof according to claim 7 , which is a 2-indoloylguanidine compound.
39. An indoloylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof according to claim 11 , wherein each of R 11 and R 12 independently represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, in which the substituent is hydroxy or —NR 6 R 7 , a C 1 -C 8 polyhaloalkyl group, a C 2 -C 6 alkenyl group, a C 3 -C 7 cycloalkyl group, a halogen atom, nitro, or a group shown by formula: —OR 3 or —NR 6 R 7 .
40. An indoloylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof according to claim 11 , wherein R 2 represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, hydroxy or a C 1 -C 6 alkoxy group.
41. An indoloylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof according to claim 12 , wherein R 2 represents a hydrogen atom, a C 1 -C 8 alkyl group, a substituted C 1 -C 8 alkyl group, hydroxy or a C 1 -C 6 alkoxy group.
42. An indoloylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof according to claim 28 , which is a 2-indoloylguanidine compound.
43. An indoloylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof according to claim 32 , wherein each of R 11 and R 12 independently represents:
a hydrogen atom;
an alkyl group having carbon atoms up to 8;
a substituted C 1 -C 8 alkyl group wherein the substituent is a hydroxy group or a group shown by —NR 6 R 7 ,
wherein each of R 6 and R 7 independently represents a hydrogen atom,
an alkyl group having carbon atoms up to 8,
a substituted C 1 -C 8 alkyl group in which the substituent means a cycloalkyl group having 3 to 7 carbon atoms, hydroxy, an alkoxy group having carbon atoms up to 6, or an alkanoyl group having carbon atom up to 8, an aryl group having carbon atoms up to 10,
a cycloalkyl group having 3 to 7 carbon atoms,
an alkanoyl group having carbon atoms up to 8, an arylalkanoyl group having carbon atoms up to 10, or an aroyl group having carbon atoms up to 11, or
a group shown by formula: —CH 2 R 60 , wherein R 60 represents an alkenyl group having carbon atoms up to 6 or an alkynyl group having 2 to 6 carbon atoms; or
R 6 and R 7 are combined together to form a saturated 5- to 7-membered cyclic group containing 1 to 3 nitrogen atoms or a saturated 5- to 7-membered cyclic group containing one nitrogen atom and one oxygen atom;
a polyhaloalkyl group having carbon atoms up to 8;
an alkenyl group having carbon atoms up to 6;
a cycloalkyl group having 3 to 7 carbon atoms;
a halogen atom;
a nitro group; or
a group shown by formula: —OR 3 or —NR 6 R 7 as defined above,
wherein R 3 represents
a hydrogen atom,
an alkyl group having carbon atoms up to 8,
a substituted C 1 -C 8 alkyl group as defined above,
a cycloalkyl group having 3 to 7 carbon atoms, or
a group shown by formula: —CH 2 R 301 wherein R 30 represents an alkenyl group having carbon atoms up to 6, or an alkynyl group having 2 to 6 carbon atoms.
44. An indoloylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof according to claim 32 , wherein R 2 represents
a hydrogen atom,
an alkyl group having carbon atoms up to 8,
a substituted C 1 -C 8 alkyl group
a hydroxy group,
or an alkoxy group having carbon atoms up to 6.
45. An indoloylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof according to claim 33 , wherein R 2 represents
a hydrogen atom,
an alkyl group having carbon atoms up to 8,
a substituted C 1 -C 8 alkyl group
a hydroxy group,
or an alkoxy group having carbon atoms up to 6.
46. A pharmaceutical composition comprising as an active ingredient an effective amount of an indoloylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof according to any one of claim 1 - 6 , 9 , 10 , 14 - 27 , 30 , 31 , 35 , or 37 and a pharmaceutically acceptable carrier.
47. A method for treating a disease caused by increased Na + /H + exchanger activity, which comprises administering to a patient a pharmaceutically effective dose of a compound according to any one of claim 1 - 6 , 9 , 10 , 14 - 27 , 30 , 31 , 35 , or 37 , or a pharmaceutically acceptable acid addition salt thereof.
48. A method according to claim 47 , wherein the disease is selected from the group consisting of hypertension, arrhythmia, angina pectoris, cardiac hypertrophy, diabetes, disorders associated with ischemia or ischemic reperfusion, cerebroischemic disorders, and diseases caused by excessive cell proliferation.Cited by (0)
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